Research Findings - Cross-Divisional Research

A NIDA DBNBR and DESPR Cross-Divisional Supported Study Highlights the CHRNA5-A3-B4 Region is a Risk Factor for Age-Dependent Nicotine Addiction

The research examined the hypothesis that associations between nicotinic acetylcholine receptor subunit gene variants and nicotine dependence assessed in adulthood would be stronger among smokers who began daily nicotine exposure during adolescence. This group examined 2,827 subjects from three European American cohorts with a mean age of 49.6 years. All were either current or previous daily cigarette smokers, with only 8% who had not smoked for at least 2 years prior to the study. Participants began daily smoking at a mean age of 17.3 and smoked 28.3 cigarettes per day for a mean of 30.7 years. The mean Fagerstrom Test of Nicotine Dependence test score was 5.7. Smokers were dichotomized into Òearly onsetÓ (age 16 or younger) and Òlate onsetÓ (age 17 or older). Using a candidate gene approach, the SNP panel screen included common coding variants and haplotypes detected in eight alpha and three beta nicotinic subunit receptor genes. Of the 2,827 long-term smokers examined, common susceptibility and protective haplotypes at the chromosome 15 CHRNA5-A3-B4 locus were associated with nicotine dependence severity (OR=1.82; 95%CI 1.39-2.39, p=2 x 10-5) in subjects who began daily smoking at or before the age of 16. This effect was not seen in subjects who began daily smoking after the age of 16, marking a period of exposure vulnerability that results in a more severe form of adult nicotine dependence. The interaction of a common genetic risk factor, age, and onset of daily smoking supports the notion that it is important to understand gene x environment x development factors. This finding needs independent replication, but it points to how genetic studies of complex disease phenotypes can bolster public health approaches to disorders such as addictions, because the risk is amenable to both intervention and prevention. Weiss, R.B., Baker, T.B., Cannon, D.S., von Niederhausern, A., Dunn, D.M., Matsunami, N., Singh, N.A., Baird, L., Coon, H., McMahon, W.M., Piper, M.E., Fiore, M.C., Scholand, M.B., Connett, J.E., Kanner, R.E., Gahring, L.C., Rogers, S.W., Hoidal, J.R., and Leppert, M.F. A Candidate Gene Approach Identifies the CHRNA5-A3-B4 Region as a Risk Factor for Age-Dependent Nicotine Addiction. PLOS Genetics, 4(7), pp. 1-11, 2008.